CN117343007A - Preparation method of lenvatinib - Google Patents

Preparation method of lenvatinib Download PDF

Info

Publication number
CN117343007A
CN117343007A CN202310825186.3A CN202310825186A CN117343007A CN 117343007 A CN117343007 A CN 117343007A CN 202310825186 A CN202310825186 A CN 202310825186A CN 117343007 A CN117343007 A CN 117343007A
Authority
CN
China
Prior art keywords
compound
reaction
temperature
mol
tert
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN202310825186.3A
Other languages
Chinese (zh)
Inventor
张贵民
文浩
鲍广龙
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shandong New Time Pharmaceutical Co Ltd
Original Assignee
Shandong New Time Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shandong New Time Pharmaceutical Co Ltd filed Critical Shandong New Time Pharmaceutical Co Ltd
Priority to CN202310825186.3A priority Critical patent/CN117343007A/en
Publication of CN117343007A publication Critical patent/CN117343007A/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention belongs to the field of pharmaceutical chemicals, and particularly relates to a preparation method of lenvatinib. The invention takes the compound 4-chloro-7-methoxyquinoline-6-formamide as a starting material, and after 3-chloro-4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) phenol is substituted, the compound reacts with 1, 2-di-tert-butyl diazacyclobutane-3-ketone to construct a urea functional group, and the obtained product reacts with bromocyclopropane after tert-butyl is removed to prepare the lenvatinib, so that the process can effectively avoid the use of phenyl chloroformate; meanwhile, the 1, 2-di-tert-butyl diazatidin-3-one protecting group exists itself, and no additional protecting group adding operation is needed; in addition, the process has short reaction steps, and can effectively shorten the production period.

Description

Preparation method of lenvatinib
Technical Field
The invention belongs to the field of pharmaceutical chemicals, and particularly relates to a preparation method of lenvatinib.
Background
Lenvatinib (lenvatinib, alias E7080), chemical name 4- [ 3-chloro-4- (cyclopropylaminocarbonyl) aminophenoxy ] -7-methoxy-6-quinolinecarboxamide, an oral multi-receptor tyrosine kinase inhibitor developed by japan sanitation corporation, was first marketed in the united states at 13, 2, 2015 under the trade name Lenvima, and was used clinically for the treatment of invasive, locally advanced or metastatic differentiated thyroid cancer, non-small cell lung cancer, and the potential treatment of other solid tumors. The market of 2018 is approved in China in 9 months, and the traditional Chinese medicine composition is started to be used for first-line treatment of unresectable liver cell liver cancer (HCC), so that the monopoly situation of sorafenib is broken, and a scheme is added for the unresectable HCC treatment. Therefore, the lenvatinib has great market prospect, and the chemical structural formula is as follows:
the preparation method comprises the steps of using 3-chloro-4-aminophenol and phenyl chloroformate as starting materials in the patents EP1683785A1, EP1698623A1, EP1797881A1, US2007/4773, US7683172B2, WO2005044788, WO2006137474, CN100450998C and CN101337930B, carrying out acylation reaction under pyridine catalysis to obtain phenyl N- (2-chloro-4-hydroxyphenyl) carbamate, then forming urea with cyclopropylamine to obtain 1- (2-chloro-4-hydroxyphenyl) -3-cyclopropylurea, and carrying out O-alkylation reaction with 4-chloro-7-methoxyquinoline-6-carboxamide to obtain lenvatinib, wherein the synthetic route is as follows:
patent CN101029022B, CN106660964a reacts 4-amino-3-chlorophenol with 4-chloro-7-methoxyquinoline-6-carboxamide, and then reacts with phenyl chloroformate and cyclopropylamine to obtain lenvatinib, the synthetic route is shown below:
the literature J.Med.chem.,2008,51 (6): 1649-1667, synthesis of Lenvantinib, J.China medicine industry, 2014,45 (6): 507-510, improvement of synthesis process of receptor tyrosine kinase inhibitor, J.China medicine chemistry, 2016,26 (1): 29-32 uses o-chloronitrobenzene or downstream intermediate thereof as starting material, 4-amino-3-chlorophenol is prepared by reduction and substitution reaction, and then urea is formed with phenyl chloroformate and cyclopropylamine to prepare the key intermediate N- (2-chloro-4-hydroxyphenyl) phenyl carbamate. In addition, malonic acid is cyclized with acetone under the catalysis of acetic anhydride and concentrated sulfuric acid to generate 2, 2-dimethyl-1, 3-dioxane-4, 6-diketone, then with 2-methoxy-4-aminobenzoic acid methyl ester under the condition of trimethyl orthoformate and isopropanol heating reflux to generate 4- [ (2, 2-dimethyl-4, 6-dioxo-1, 3-dioxane-5-methylene) amino ] -2-methoxybenzoic acid methyl ester, then rearrangement is carried out under the condition of diphenyl ether heating to generate 7-methoxy-4-oxo-1, 4-dihydro quinoline-6-carboxylic acid methyl ester, and then thionyl chloride is carried out to generate 4-chloro-7-methoxy quinoline-6-carboxylic acid methyl ester, then another key intermediate 4-chloro-7-methoxy quinoline-6-carboxamide is obtained through aminolysis reaction, and finally, the two key intermediates are catalyzed by cesium carbonate and activated copper powder to generate the target compound, wherein the synthetic route is shown as follows:
patent CN109456267A and literature Lenvantinib synthesis, journal of Chinese medicinal chemistry, 2015,25 (4): 285-288 uses 4-aminosalicylic acid as raw material, methyl sulfate is methylated to obtain 4-amino-2-methoxybenzoate, then the 4-amino-2-methoxybenzoate is condensed with 2, 2-dimethyl-1, 3-dioxane-4, 6-dione, and the 4-chloro-7-methoxyquinoline-6-formamide is obtained through high temperature cyclization, chloro-amination. Finally, the two intermediates react under the alkaline condition of potassium carbonate and tertiary butyl alcohol potassium to obtain the target product. However, the relevant intermediate after the condensation of the route has low yield, is unstable and is easy to decompose, and the process has longer synthetic route and lower overall yield, and the synthetic route is shown as follows:
patent CN108658859a uses m-chlorophenol as raw material, after heating reaction with nitrifying reagent, 3-chloro-4-nitrophenol is obtained by simple purification, then 4-chloro-7-methoxyquinoline-6-carboxamide reacts with 4-chloro-7-methoxyquinoline-6-carboxamide in organic solvent by heating reaction to generate 4- (3-chloro-4-nitrophenoxy) -7-methoxy-6-quinolinecarboxamide, then nitro is reduced, and then reacts with phenyl chloroformate and cyclopropylamine successively to generate lenvatinib, the synthetic route is shown as follows:
US7253286B2 is prepared from 3-chloro-4-cyanoaniline by methyl-treating, condensing with Maidelumid, heating in biphenyl-biphenyl ether mixed solvent for ring closure, hydrolyzing, chloro-treating, and ammonifying to obtain 4-chloro-7-methoxyquinoline-6-formamide. In addition, 3-chloro-4-aminophenol and phenyl chloroformate are used as starting materials according to the aforementioned patent method, and then phenyl N- (2-chloro-4-hydroxyphenyl) carbamate is obtained through acylation reaction, and then cyclopropylamine is used for forming urea to obtain another key intermediate 1- (2-chloro-4-hydroxyphenyl) -3-cyclopropylurea. The final two intermediates are catalyzed by potassium tert-butoxide to obtain target compounds, and the synthetic route is shown as follows:
however, the above routes all adopt phenyl chloroformate with certain toxicity, and the phenyl chloroformate has high toxicity, is not easy to be purchased in the market, is relatively complex to prepare, and can generate phenol with relatively high toxicity in subsequent reactions.
Patent CN104876864a uses 4-amino-3-chlorophenol as starting material, and obtains (2-chloro-4-hydroxy-phenyl) carbamic acid tert-butyl ester through Boc (tert-butyloxycarbonyl) protection of amino group, then reacts with 4-chloro-7-methoxyquinoline-6-formamide under alkaline condition of cesium carbonate to obtain 4- (6-carbamoyl-7-methoxyquinoline-4-oxy) -2-chlorobenzoic acid tert-butyl ester, and then removes Boc in hydrochloric acid methanol solution and reacts with cyclopropylamine and CDI to obtain the target product. The process involves pre-performing Boc protection of amino group on 4-amino-3-chlorophenol, and then participating in the rest reaction, wherein on one hand, the protection of amino group can reduce side reaction, on the other hand, phenolic hydroxyl group exists in molecule, the activity is higher under alkaline condition, and Boc is adopted 2 The O acylation speed is high, so that the selectivity of amino protection is poor. In addition, the resulting up-protection and deprotection increases the reaction steps and purification operations, reduces overall yields, affects industrialization efficiency, and the synthetic route is as follows:
patent CN109734661a uses 4-cyano-3-hydroxyaniline as starting material, methyl carbonate is used to make methylation, and then the methyl carbonate is used to make the methyl carbonate undergo the process of reaction and oximation at room temperature, under the condition of PPA (polyphosphoric acid), the ring-closing reaction is formed into 6-cyano-7-methoxy-4-quinolinone, under the action of thionyl chloride, 6-cyano-7-methoxy-4-chloropinone is formed, under the condition of acidity, the cyano group is hydrolyzed to synthesize one intermediate 6-formamido-7-methoxy-4-chloroquinoline of lenvatinib. Then 4-hydroxy-2-chloroaniline and cyanogen bromide are subjected to low temperature to form 4-hydroxy-2-chlorocyanidate, and 4-hydroxy-2-chlorocyanidate and bromopropane are subjected to Ritter reaction to synthesize the other key intermediate 1- (2-chloro-4-hydroxyphenyl) -3-cyclopropylurea of the lenvatinib. Finally, two intermediates of 6-formamido-7-methoxy-4-chloroquinoline and 1- (2-chloro-4-hydroxyphenyl) -3-cyclopropylurea are subjected to alkylation reaction in an alkaline environment to prepare the lenvatinib. However, the starting material 4-cyano-3-hydroxyaniline in the route is difficult to obtain, the reaction route is long in whole, the total yield is low, and the industrialized mass production is difficult, and the synthetic route is as follows:
in summary, in view of the disadvantages of the existing preparation method of the lenvatinib in the aspects of safe process, complicated operation, low yield, high production cost and the like, the research and the search of a reaction route which is mild in reaction condition, simple and convenient in operation process, high in product yield and purity and low in production cost and is suitable for industrialized production of the lenvatinib still need to be solved.
Disclosure of Invention
Aiming at the complicated operation of pre-protecting and then deprotecting Boc of amino in the existing preparation technology of the lenvatinib, the invention provides a novel synthesis method of the lenvatinib. The method can avoid the complicated deprotection operation, has higher purity and yield, and is suitable for industrial production.
The specific technical scheme of the invention is as follows:
a method for preparing lenvatinib, which comprises the following steps:
step 1: at room temperature, compound SM-1,Adding compound SM-2 and alkali A into reaction solvent A, controlling temperature T A After the reaction is finished, preparing an intermediate compound I-1 through post-treatment;
preferably, the base A in the step 1 is selected from one of potassium hydroxide, N-diisopropylethylamine, triethylamine, N-methylmorpholine, potassium carbonate, potassium tert-butoxide and sodium methoxide, preferably potassium hydroxide.
Preferably, the reaction solvent a in step 1 is one of N, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, acetonitrile or N-methylpyrrolidone, preferably dimethylsulfoxide.
Preferably, the molar ratio of compound SM-1 to compound SM-2 to base A in step 1 is 1:1.1 to 1.6:2.5 to 5.0, preferably 1:1.2:3.0.
preferably, the temperature T is controlled as described in step 1 A 60 to 100℃and preferably 70 to 75 ℃.
In a preferred embodiment, after the reaction in step 1 is completed, a post-treatment operation is performed, specifically: cooling the reaction liquid to room temperature, adding purified water, stirring for crystallization, continuously cooling to 5-10 ℃, stirring for crystallization, filtering, and drying the obtained filter cake under reduced pressure to obtain the compound I-1.
Step 2: adding compound I-1 and organolithium into tetrahydrofuran, and controlling temperature T B After stirring evenly, adding compound SM-3, continuing to control temperature T B After stirring evenly, adding catalyst and continuing controlling temperature T B After the reaction is finished, preparing an intermediate compound I-2 through post-treatment;
preferably, the organolithium described in step 2 is selected from one or a combination of n-butyllithium (n-BuLi), sec-butyllithium (s-BuLi), phenyllithium (PhLi), preferably n-butyllithium.
Preferably, the catalyst in step 2 is selected from the group consisting of cuprous bromide (CuBr), cuprous chloride (CuCl), cupric bromide (CuBr) 2 ) Preferably cuprous bromide, or a combination thereof.
Preferably, the molar ratio of the compound I-1 to the compound SM-3, the organolithium and the catalyst in the step 2 is 1:1.3 to 2.0:1.0 to 1.4:0.8 to 1.3, preferably 1:1.6:1.1:1.0.
preferably, the reaction temperature T described in step 2 B Is 10 to 30℃and preferably 20 to 25 ℃.
In a preferred embodiment, after the reaction in step 2 is completed, a post-treatment operation is performed, specifically: cooling the reaction liquid to room temperature, quenching the reaction with saturated ammonium chloride solution, filtering, adding purified water into the filtrate, extracting with an organic solvent, combining organic phases, washing with saturated saline solution, and concentrating the organic phases under reduced pressure until the organic phases are dried to obtain an intermediate compound I-2.
Step 3: adding compound I-2 into trifluoroacetic acid (TFA), controlling temperature T C After the reaction is finished, the reaction solution is decompressed and concentrated to remove most of the solvent, then the reaction solution is neutralized to pH value of more than 7 by saturated sodium bicarbonate, the organic solvent is extracted, the organic phase is combined, the organic phase is washed by saturated saline, and the organic phase is decompressed and concentrated to dryness to obtain the intermediate compound I-3.
Preferably, the feeding mass volume ratio of the compound I-2 to the trifluoroacetic acid in the step 3 is 1:6 to 12 g/ml, preferably 1:8,g/ml.
Preferably, the reaction temperature T described in step 3 C 50 to 69℃and preferably 64 to 69 ℃.
Step 4: under the protection of inert gas, adding the compound I-3, bromocyclopropane, alkali D, catalyst and ligand into the reaction solvent D, and controlling the temperature T D And after the reaction is finished, carrying out post-treatment to obtain the compound I.
Preferably, the base D in step 4 is selected from one or a combination of potassium phosphate, cesium carbonate, potassium carbonate, sodium tert-butoxide, preferably cesium carbonate.
Preferably, the catalyst in step 4 is selected from one or a combination of palladium acetate and palladium chloride, preferably palladium acetate.
Preferably, the ligand in step 4 is 2- (di-tert-butylphosphine) -3, 6-dimethoxy-2 '-4' -6 '-tri-1-propyl-1, 1' -biphenyl, and the chemical structural formula thereof is shown as follows:
preferably, the feeding mole ratio of the I-3 to the bromocyclopropane, the alkali D, the catalyst and the ligand in the step 4 is 1:1.05 to 1.5:1.0 to 1.8:0.03 to 0.08:0.1 to 0.2, preferably 1:1.2:1.4:0.05:0.15.
preferably, the reaction solvent D in the step 4 is one or a combination of dimethyl sulfoxide, 1, 4-dioxane and water.
Preferably, the reaction temperature T described in step 4 D The temperature is 80 to 110℃and preferably 90 to 95 ℃.
Preferably, the inert gas in step 4 is one of nitrogen and argon, preferably argon.
In a preferred embodiment, after the reaction in step 4 is completed, a post-treatment operation is performed, specifically: the reaction solution is filtered by diatomite while hot, the filtrate is cooled to room temperature, purified water is added, the organic solvent is used for extraction, the organic phases are combined, the saturated saline water is used for washing, and the organic phases are concentrated to dryness under reduced pressure, thus obtaining the target compound I.
In a preferred scheme, the organic solvent for extraction in the post-treatment in the steps 2, 3 and 4 is dichloromethane,
chloroform, methyl tert-butyl ether or a combination thereof, preferably dichloromethane.
The synthetic route is as follows:
the invention has the beneficial effects that:
(1) the invention provides a novel method for preparing lenvatinib (I), which takes a compound SM-1 as a starting material, and after SM-2 substitution, the compound reacts with SM-3 to construct a urea functional group, and after tert-butyl is removed, the compound reacts with bromocyclopropane to prepare a target product.
(2) The process can effectively avoid the use of phenyl chloroformate; meanwhile, the SM-3 protecting group exists, and the operation of adding an additional protecting group is not needed; in addition, the process has short reaction steps, and can effectively shorten the production period; the target product prepared by the process has higher yield and purity, and is suitable for industrial scale-up production.
Detailed Description
The invention is further illustrated by the following examples, with the understanding that: the examples of the present invention are intended to be illustrative of the invention and not to be limiting of the invention, so that simple modifications to the invention which are based on the method of the invention are within the scope of the invention as claimed.
The starting materials and catalysts used may be prepared or purchased according to the prior art and in the examples below, the various processes and methods not described in detail are conventional methods known in the art.
The structural identification data for the related compounds are as follows:
ESI-HRMS(m/z):455.1473[M+H] + ； 1 H NMR(400MHz,DMSO-d 6 )δ8.86(d,J＝7.5Hz,
1H),8.63(s,1H),7.90(s,2H),7.73(s,1H),7.62(d,J＝7.5Hz,1H),6.94(d,J＝1.4Hz,1H),6.59～6.48(m,2H),4.02(s,3H),1.35(s,12H)； 13 C NMR(101MHz,DMSO-d 6 )δ168.40,161.46,161.38,152.37,151.22,148.63,131.07,127.59,124.51,121.15,119.68,118.94,118.15,115.92,111.36,106.78,88.42,56.26,22.42。
ESI-HRMS(m/z):499.2038[M+H] + ； 1 H NMR(400MHz,DMSO-d 6 )δ9.01(d,J＝7.5Hz,
1H),8.52(s,1H),7.92(s,2H),7.81(d,J＝7.5Hz,1H),7.75(s,1H),7.23(d,J＝7.6Hz,1H),7.11(d,J＝1.4Hz,1H),6.74(dd,J＝7.6,1.4Hz,1H),4.00(s,3H),3.61(s,1H),1.41(d,J＝6.9Hz,18H)； 13 C NMR(101MHz,DMSO-d 6 )δ168.98,161.81,161.26,155.14,152.36,151.27,148.35,137.64,135.13,129.64,127.57,122.05,120.39,119.12,115.49,111.62,106.08,57.41,56.52,53.14,29.74,28.68。
ESI-HRMS(m/z):387.0653[M+H] + ； 1 H NMR(400MHz,DMSO-d 6 )δ8.62(d,J＝7.5Hz,
1H),8.54(s,1H),7.92(s,1H),7.90(s,2H),7.60(s,1H),7.53(d,J＝7.5Hz,1H),7.24(d,J＝1.4Hz,1H),7.10(d,J＝7.6Hz,1H),6.65(dd,J＝7.6,1.4Hz,1H),6.10(s,2H),4.00(s,3H)； 13 CNMR(101MHz,DMSO-d 6 )δ168.74,161.89,161.24,156.05,153.42,152.93,148.67,131.18,129.75,127.56,122.66,121.28,119.84,119.35,115.34,111.27,106.48,56.63。
ESI-HRMS(m/z):427.1164[M+H] + ； 1 H NMR(600MHz,DMSO-d 6 )δ：8.65(d,J＝5.2Hz,
1H),8.57(s,1H),8.28(d,J＝9.1Hz,1H),7.90(s,1H),7.64(s,1H),7.58(s,1H),7.52(s,1H),7.48(d,J＝2.8Hz,1H),7.24(dd,J＝9.1,2.8Hz,1H),7.20(d,J＝2.8Hz,1H),6.53(d,J＝5.2Hz,1H),4.04(s,3H),2.54～2.62(m,1H),0.64～0.68(m,2H),0.41～0.45(m,2H)； 13 CNMR(151MHz,DMSO-d 6 )δ：165.40,161.96,159.48,155.38,153.29,152.21,148.37,134.94,125.19,124.42,122.46,121.81,121.56,120.07,114.23,107.08,102.23,56.79,22.96,6.92。
the invention adopts HPLC to measure the purity of the lenvatinib, and the chromatographic conditions are as follows:
chromatographic column: YMC-Pack Pro C 18 Columns (4.6 mm. Times.150 mm,3 μm) or columns of comparable performance;
mobile phase: mobile phase a: water-acetonitrile-perchloric acid (70%) (990:10:1) (V: V); mobile phase B: water-acetonitrile-perchloric acid (70%) (100:900:1) (V: V: V)
Column temperature: 25 ℃; detection wavelength: 252nm; flow rate: 1.0ml/min; sample injection amount: 10 μl;
wherein, the retention time of the lenvatinib is about 23.0 min.
Elution gradients are shown in table 1:
TABLE 1 elution gradient table
Synthesis of intermediate compound I-1:
example 1
At room temperature, adding compound SM-1 (71.00 g,0.3 mol), compound SM-2 (91.63 g,0.36 mol) and potassium hydroxide (50.49 g,0.9 mol) into dimethyl sulfoxide (650 ml), controlling the temperature to 70-75 ℃ for reaction, cooling the reaction liquid to room temperature after the detection reaction is finished, adding purified water (5000 ml), stirring for crystallization, continuously cooling to 5-10 ℃, stirring for crystallization for 1-2 h, filtering, and drying the obtained filter cake under reduced pressure to obtain compound I-1, wherein the yield is 95.3% and the purity is 99.85%.
Example 2
At room temperature, adding compound SM-1 (71.00 g,0.3 mol), compound SM-2 (83.99 g,0.33 mol) and N, N-diisopropylethylamine (116.32 g,0.9 mol) into dimethyl sulfoxide (650 ml), controlling the temperature to be 70-75 ℃, reacting, cooling the reaction liquid to room temperature after the detection reaction is finished, adding purified water (5000 ml), stirring and crystallizing, continuously cooling to 5-10 ℃, stirring and crystallizing for 1-2 h, filtering, decompressing and drying the obtained filter cake, and obtaining compound I-1, wherein the yield is 92.5% and the purity is 99.68%.
Example 3
At room temperature, adding compound SM-1 (71.00 g,0.3 mol), compound SM-2 (122.16 g,0.48 mol) and triethylamine (91.07 g,0.9 mol) into N, N-dimethylacetamide (650 ml), controlling the temperature to be 70-75 ℃ for reaction, cooling the reaction liquid to room temperature after the detection reaction is finished, adding purified water (5000 ml) for stirring crystallization, continuously cooling to 5-10 ℃, stirring for crystallization for 1-2 h, filtering, and drying the obtained filter cake under reduced pressure to obtain compound I-1, wherein the yield is 93.1% and the purity is 99.60%.
Example 4
At room temperature, adding compound SM-1 (71.00 g,0.3 mol), compound SM-2 (91.63 g,0.36 mol) and potassium tert-butoxide (84.16 g,0.75 mol) into acetonitrile (650 ml), controlling the temperature to be 60-65 ℃ for reaction, cooling the reaction liquid to room temperature after the detection reaction is finished, adding purified water (5000 ml), stirring for crystallization, continuously cooling to 5-10 ℃ for stirring for crystallization for 1-2 h, filtering, and drying the obtained filter cake under reduced pressure to obtain compound I-1, wherein the yield is 93.6% and the purity is 99.70%.
Example 5
At room temperature, adding compound SM-1 (71.00 g,0.3 mol), compound SM-2 (91.63 g,0.36 mol) and sodium methoxide (81.03 g,1.5 mol) into dimethyl sulfoxide (650 ml), controlling the temperature to 95-100 ℃ for reaction, cooling the reaction liquid to room temperature after detection reaction, adding purified water (5000 ml), stirring for crystallization, continuously cooling to 5-10 ℃ for stirring for crystallization for 1-2 h, filtering, and drying the obtained filter cake under reduced pressure to obtain compound I-1, wherein the yield is 94.3% and the purity is 99.62%.
Example 6
Adding compound SM-1 (71.00 g,0.3 mol), compound SM-2 (76.35 g,0.3 mol) and N-methylmorpholine (70.81 g,0.7 mol) into N-methylpyrrolidone (650 ml) at room temperature, controlling the temperature to be 55-60 ℃, reacting, cooling the reaction liquid to room temperature after the detection reaction is finished, adding purified water (5000 ml), stirring and crystallizing, continuously cooling to 5-10 ℃, stirring and crystallizing for 1-2 h, filtering, decompressing and drying the obtained filter cake, and obtaining compound I-1 with the yield of 86.3% and the purity of 98.85%.
Example 7
Adding compound SM-1 (71.00 g,0.3 mol), compound SM-2 (137.44 g,0.54 mol) and potassium carbonate (210.08 g,1.52 mol) into N-methylpyrrolidone (750 ml) at room temperature, controlling the temperature to be 100-105 ℃ for reaction, cooling the reaction solution to room temperature after detection reaction, adding purified water (5000 ml) for stirring crystallization, continuously cooling to 5-10 ℃ for stirring crystallization for 1-2 h, filtering, and drying the obtained filter cake under reduced pressure to obtain compound I-1, wherein the yield is 88.9% and the purity is 98.56%.
Synthesis of intermediate compound I-2:
example 8
Adding compound I-1 (90.94 g,0.2 mol) and n-butyllithium (1.6 mol/L in Hexane,137.5ml,0.22 mol) into tetrahydrofuran (750 ml), stirring uniformly at a temperature of 20-25 ℃, adding compound SM-3 (54.48 g,0.32 mol) after stirring uniformly at a temperature of 20-25 ℃, adding cuprous bromide (28.69 g,0.2 mol) after stirring uniformly at a temperature of 20-25 ℃, continuing to react at a temperature of 20-25 ℃, cooling the reaction solution to room temperature after detection reaction, quenching the reaction solution with saturated ammonium chloride solution, filtering, adding purified water (6000 ml) into the filtrate, extracting dichloromethane (2500 ml x 3), merging the organic phases, washing the saturated saline (2500 ml x 2), concentrating the organic phases under reduced pressure until the organic phases are dried, thus obtaining intermediate compound I-2, wherein the yield is 98.6%, and the purity is 99.95%.
Example 9
Adding compound I-1 (90.94 g,0.2 mol) and n-butyllithium (1.6 mol/L in Hexane,125ml,0.2 mol) into tetrahydrofuran (750 ml), stirring uniformly at 20-25 ℃ and then adding compound SM-3 (54.48 g,0.32 mol), stirring uniformly at 20-25 ℃ continuously, adding cuprous chloride (19.80 g,0.2 mol), continuing to react at 20-25 ℃, cooling the reaction solution to room temperature after the detection reaction is finished, quenching the reaction by using saturated ammonium chloride solution, filtering, adding purified water (6000 ml) into the filtrate, extracting dichloromethane (2500 ml multiplied by 3), merging organic phases, washing saturated saline (2500 ml multiplied by 2), concentrating the organic phases under reduced pressure until the organic phases are dried, namely the intermediate compound I-2, wherein the yield is 95.3% and the purity is 99.74%.
Example 10
Adding compound I-1 (90.94 g,0.2 mol) and n-butyllithium (1.6 mol/L in Hexane,175ml,0.28 mol) into tetrahydrofuran (750 ml), stirring uniformly at 20-25 ℃ under controlled temperature, adding compound SM-3 (54.48 g,0.32 mol), stirring uniformly at 20-25 ℃ under controlled temperature, adding copper bromide (44.67 g,0.2 mol), continuing to react at 20-25 ℃, cooling the reaction solution to room temperature after detection reaction, quenching reaction with saturated ammonium chloride solution, filtering, adding purified water (6000 ml) into the filtrate, extracting dichloromethane (2500 ml×3), merging organic phases, washing saturated saline (2500 ml×2), concentrating the organic phases under reduced pressure until the organic phases are dried, namely intermediate compound I-2, wherein the yield is 96.2%, and the purity is 99.63%.
Example 11
Adding compound I-1 (90.94 g,0.2 mol) and sec-butyllithium (1.0 mol/L in Hexane,220ml,0.22 mol) into tetrahydrofuran (750 ml), stirring uniformly at 20-25 ℃ and then adding compound SM-3 (44.27 g,0.26 mol), stirring uniformly at 20-25 ℃ continuously, adding cuprous bromide (28.69 g,0.2 mol), continuing to react at 20-25 ℃, cooling the reaction solution to room temperature after the detection reaction is finished, quenching the reaction with saturated ammonium chloride solution, filtering, adding purified water (6000 ml) into the filtrate, extracting dichloromethane (2500 ml multiplied by 3), merging the organic phase, washing with saturated saline (2500 ml multiplied by 2), concentrating the organic phase under reduced pressure until the organic phase is dried, thus obtaining intermediate compound I-2, wherein the yield is 97.3% and the purity is 99.89%.
Example 12
Adding compound I-1 (90.94 g,0.2 mol) and phenyl lithium (1.0 mol/L in ethyl ether,220ml,0.22 mol) into tetrahydrofuran (750 ml), stirring uniformly at a temperature of 20-25 ℃, adding compound SM-3 (68.10 g,0.40 mol) after stirring uniformly at a temperature of 20-25 ℃, adding cuprous bromide (28.69 g,0.2 mol) after stirring uniformly at a temperature of 20-25 ℃, continuing to react at a temperature of 20-25 ℃, cooling the reaction solution to room temperature after detection reaction, quenching the reaction with saturated ammonium chloride solution, filtering, adding purified water (6000 ml) into the filtrate, extracting dichloromethane (2500 ml×3), merging the organic phases, washing the saturated saline (2500 ml×2), concentrating the organic phases under reduced pressure until the organic phases are dried, namely the intermediate compound I-2, wherein the yield is 95.6%, and the purity is 99.65%.
Example 13
Adding compound I-1 (90.94 g,0.2 mol) and n-butyllithium (1.6 mol/L in Hexane,137.5ml,0.22 mol) into tetrahydrofuran (750 ml), stirring uniformly at a temperature of 10-15 ℃, adding compound SM-3 (54.48 g,0.32 mol) after stirring uniformly at a temperature of 10-15 ℃, adding cuprous bromide (22.95 g,0.16 mol) after stirring uniformly at a temperature of 10-15 ℃, continuing to react at a temperature of 10-15 ℃, cooling the reaction liquid to room temperature after detection reaction, quenching the reaction liquid by using saturated ammonium chloride solution, filtering, adding purified water (6000 ml) into the filtrate, extracting dichloromethane (2500 ml multiplied by 3), merging the organic phases, washing the saturated saline (2500 ml multiplied by 2), concentrating the organic phases under reduced pressure until the organic phases are dried, namely the intermediate compound I-2, wherein the yield is 96.3%, and the purity is 99.80%.
Example 14
Adding compound I-1 (90.94 g,0.2 mol) and n-butyllithium (1.6 mol/L in Hexane,137.5ml,0.22 mol) into tetrahydrofuran (750 ml), stirring uniformly at 25-30 ℃ and then adding compound SM-3 (54.48 g,0.32 mol), stirring uniformly at 25-30 ℃ continuously, adding cuprous bromide (37.30 g,0.26 mol), continuing to react at 25-30 ℃, cooling the reaction solution to room temperature after detection reaction, quenching the reaction with saturated ammonium chloride solution, filtering, adding purified water (6000 ml) into the filtrate, extracting dichloromethane (2500 ml multiplied by 3), merging organic phases, washing the saturated saline (2500 ml multiplied by 2), concentrating the organic phases under reduced pressure until the organic phases are dried, namely the intermediate compound I-2, wherein the yield is 96.8%, and the purity is 99.65%.
Example 15
Adding compound I-1 (90.94 g,0.2 mol) and n-butyllithium (1.6 mol/L in Hexane,112.5ml,0.18 mol) into tetrahydrofuran (750 ml), stirring uniformly at a temperature of 5-10 ℃, adding compound SM-3 (34.05 g,0.2 mol) after stirring uniformly at a temperature of 5-10 ℃, adding cuprous bromide (17.21 g,0.12 mol) after stirring uniformly at a temperature of 5-10 ℃, continuing to react at a temperature of 5-10 ℃, cooling the reaction solution to room temperature after detection reaction, quenching the reaction with saturated ammonium chloride solution, filtering, adding purified water (6000 ml) into the filtrate, extracting dichloromethane (2500 ml x 3), merging the organic phases, washing the saturated saline (2500 ml x 2), concentrating the organic phases under reduced pressure until the organic phases are dried, namely the intermediate compound I-2, wherein the yield is 85.6%, and the purity is 98.85%.
Example 16
Adding compound I-1 (90.94 g,0.2 mol) and n-butyllithium (1.6 mol/L in Hexane,200ml,0.32 mol) into tetrahydrofuran (750 ml), uniformly stirring at a temperature of 30-35 ℃, adding compound SM-3 (74.91 g,0.44 mol) after uniformly stirring at a temperature of 30-35 ℃, adding cuprous bromide (43.04 g,0.3 mol) after continuously stirring at a temperature of 30-35 ℃, continuously reacting at a temperature of 30-35 ℃, cooling the reaction solution to room temperature after detecting the reaction, quenching the reaction with saturated ammonium chloride solution, filtering, adding purified water (6000 ml) into the filtrate, extracting dichloromethane (2500 ml multiplied by 3), merging the organic phases, washing the saturated saline (2500 ml multiplied by 2), and concentrating the organic phases under reduced pressure until the organic phases are dried to obtain intermediate compound I-2, wherein the yield is 88.2% and the purity is 98.35%.
Synthesis of intermediate compound I-3:
example 17
Compound I-2 (49.90 g,0.1 mol) was added to trifluoroacetic acid (TFA, 400 ml) and reacted at a temperature of 64 to 69 ℃, after the completion of the detection reaction, the reaction solution was concentrated under reduced pressure to remove most of the solvent, and then neutralized with saturated sodium bicarbonate to a pH of more than 7, extracted with dichloromethane (800 ml×3), the organic phases were combined, washed with saturated brine (800 ml×2), and concentrated under reduced pressure to dryness to obtain intermediate compound I-3 in a yield of 98.6% and a purity of 99.92%.
Example 18
Compound I-2 (49.90 g,0.1 mol) was added to trifluoroacetic acid (TFA, 300 ml) and reacted at a temperature of 50-55 ℃, after the completion of the detection reaction, the reaction solution was concentrated under reduced pressure to remove most of the solvent, and then neutralized with saturated sodium bicarbonate to a pH of more than 7, extracted with dichloromethane (800 ml×3), the organic phases were combined, washed with saturated brine (800 ml×2), and concentrated under reduced pressure to dryness to obtain intermediate compound I-3 in a yield of 96.3% and a purity of 99.75%.
Example 19
Compound I-2 (49.90 g,0.1 mol) was added to trifluoroacetic acid (TFA, 600 ml), the temperature was controlled at 65-69 ℃ and after the completion of the reaction, the reaction solution was concentrated under reduced pressure to remove most of the solvent, then neutralized with saturated sodium bicarbonate to pH above 7, extracted with dichloromethane (800 ml×3), the organic phases were combined, washed with saturated brine (800 ml×2), and concentrated under reduced pressure to dryness to give intermediate compound I-3 in a yield of 97.1% and a purity of 99.61%.
Example 20
Compound I-2 (49.90 g,0.1 mol) was added to trifluoroacetic acid (TFA, 250 ml) and reacted at 45-50 ℃ under controlled temperature, after the completion of the detection reaction, the reaction solution was concentrated under reduced pressure to remove most of the solvent, and then neutralized with saturated sodium bicarbonate to pH greater than 7, extracted with dichloromethane (800 ml×3), the organic phases were combined, washed with saturated brine (800 ml×2), and concentrated under reduced pressure to dryness to obtain intermediate compound I-3 in a yield of 87.6% and a purity of 98.92%.
Example 21
Compound I-2 (49.90 g,0.1 mol) was added to trifluoroacetic acid (TFA, 650 ml) and reacted at a temperature of 69 to 74 ℃, after the completion of the detection reaction, the reaction solution was concentrated under reduced pressure to remove most of the solvent, and then neutralized with saturated sodium bicarbonate to a pH of more than 7, extracted with dichloromethane (800 ml×3), the organic phases were combined, washed with saturated brine (800 ml×2), and concentrated under reduced pressure to dryness to obtain intermediate compound I-3 in a yield of 89.3% and a purity of 98.80%.
Synthesis of Compound I:
example 22
Under the protection of argon, compound I-3 (19.34 g,0.05 mol), bromocyclopropane (7.26 g,0.06 mol), cesium carbonate (22.81 g,0.07 mol), palladium acetate (0.56 g,2.5 mmol), 2- (di-tert-butylphosphine) -3, 6-dimethoxy-2 '-4' -6 '-tri-1-propyl-1, 1' -biphenyl (3.64 g,7.5 mmol) are added into 1, 4-dioxane (200 ml), the temperature is controlled to be between 90 and 95 ℃, after the detection reaction is finished, the reaction solution is filtered while hot with diatomite, the filtrate is cooled to room temperature, the mixture is added into purified water (1500 ml), dichloromethane (500 ml multiplied by 3) is extracted, an organic phase is combined, saturated saline (500 ml multiplied by 2) is washed, and the organic phase is concentrated to be dry under reduced pressure, thus obtaining the target compound I, the yield is 98.8%, and the purity is 99.93%.
Example 23
Under the protection of argon, compound I-3 (19.34 g,0.05 mol), bromocyclopropane (6.29 g,0.052 mol), potassium phosphate (14.86 g,0.07 mol), palladium acetate (0.56 g,2.5 mmol) and 2- (di-tert-butylphosphine) -3, 6-dimethoxy-2 '-4' -6 '-tri-1-propyl-1, 1' -biphenyl (3.64 g,7.5 mmol) are added into dimethyl sulfoxide (200 ml), the temperature is controlled to be 90-95 ℃ for reaction, after the detection reaction is finished, the reaction solution is filtered while hot through diatomite, the filtrate is cooled to room temperature, purified water (1500 ml) is added for extraction, dichloromethane (500 ml multiplied by 3) is combined, saturated saline (500 ml multiplied by 2) is used for washing, and the organic phase is decompressed and concentrated to be dried to obtain the target compound I, the yield is 95.3%, and the purity is 99.68%.
Example 24
Under the protection of argon, compound I-3 (19.34 g,0.05 mol), bromocyclopropane (9.07 g,0.075 mol), potassium carbonate (9.67 g,0.07 mol), palladium acetate (0.56 g,2.5 mmol) and 2- (di-tert-butylphosphine) -3, 6-dimethoxy-2 '-4' -6 '-tri-1-propyl-1, 1' -biphenyl (3.64 g,7.5 mmol) are added into water (200 ml), the temperature is controlled to be 90-95 ℃ for reaction, after the detection reaction is finished, the reaction solution is filtered while the reaction solution is hot and is filled with diatomite, the filtrate is cooled to room temperature, added into purified water (1500 ml), dichloromethane (500 ml multiplied by 3) is extracted, an organic phase is combined, saturated saline (500 ml multiplied by 2) is washed, and the organic phase is concentrated to be dry under reduced pressure, thus obtaining the target compound I, the yield is 96.2%, and the purity is 99.58%.
Example 25
Under the protection of argon, compound I-3 (19.34 g,0.05 mol), bromocyclopropane (7.26 g,0.06 mol), cesium carbonate (16.29 g,0.05 mol), palladium chloride (0.44 g,2.5 mmol), 2- (di-tert-butylphosphine) -3, 6-dimethoxy-2 '-4' -6 '-tri-1-propyl-1, 1' -biphenyl (3.64 g,7.5 mmol) are added into 1, 4-dioxane (200 ml), the temperature is controlled to be 80-85 ℃, after the detection reaction is finished, the reaction solution is filtered while hot with diatomite, the filtrate is cooled to room temperature, purified water (1500 ml) is added for extraction, dichloromethane (500 ml multiplied by 3) is combined, an organic phase is washed with saturated saline (500 ml multiplied by 2), and the organic phase is concentrated to be dry under reduced pressure, thus obtaining the target compound I, the yield is 96.7%, and the purity is 99.78%.
Example 26
Under the protection of argon, compound I-3 (19.34 g,0.05 mol), bromocyclopropane (7.26 g,0.06 mol), cesium carbonate (29.32 g,0.09 mol), palladium chloride (0.44 g,2.5 mmol) and 2- (di-tert-butylphosphine) -3, 6-dimethoxy-2 '-4' -6 '-tri-1-propyl-1, 1' -biphenyl (3.64 g,7.5 mmol) are added into dimethyl sulfoxide (200 ml), the temperature is controlled to be 105-110 ℃, after the detection reaction is finished, the reaction solution is filtered while the reaction solution is hot through diatomite, the filtrate is cooled to room temperature, purified water (1500 ml) is added for extraction, an organic phase is combined, saturated brine (500 ml multiplied by 2) is washed, and the organic phase is concentrated to be dry under reduced pressure, thus obtaining the target compound I, the yield is 97.1%, and the purity is 99.66%.
Example 27
Under the protection of argon, the compound I-3 (19.34 g,0.05 mol), bromocyclopropane (7.26 g,0.06 mol), sodium tert-butoxide (6.73 g,0.07 mol), palladium acetate (0.34 g,1.5 mmol) and 2- (di-tert-butylphosphine) -3, 6-dimethoxy-2 '-4' -6 '-tri-1-propyl-1, 1' -biphenyl (2.42 g,5.0 mmol) are added into 1, 4-dioxane (200 ml), the temperature is controlled to be between 90 and 95 ℃, after the detection reaction is finished, the reaction solution is filtered while hot by diatomite, the filtrate is cooled to room temperature, the filtrate is added into purified water (1500 ml), chloroform (500 ml multiplied by 3) is extracted, the organic phases are combined, saturated brine (500 ml multiplied by 2) is washed, and the organic phase is concentrated to be dry, thus obtaining the target compound I, the yield is 96.4%, and the purity is 99.75%.
Example 28
Under the protection of argon, compound I-3 (19.34 g,0.05 mol), bromocyclopropane (7.26 g,0.06 mol), cesium carbonate (22.81 g,0.07 mol), palladium acetate (0.90 g,4.0 mmol) and 2- (di-tert-butylphosphine) -3, 6-dimethoxy-2 '-4' -6 '-tri-1-propyl-1, 1' -biphenyl (4.85 g,10 mmol) are added into 1, 4-dioxane (200 ml), the temperature is controlled to 100-105 ℃, after the reaction is detected, the reaction solution is filtered while hot through diatomite, the filtrate is cooled to room temperature, purified water (1500 ml) is added for extraction, methyl tert-butyl ether (500 ml multiplied by 3) is combined, an organic phase is washed with saturated saline (500 ml multiplied by 2), and the organic phase is concentrated to dryness, thus obtaining the target compound I, the yield is 97.0%, and the purity is 99.66%.
Example 29
Under the protection of argon, compound I-3 (19.34 g,0.05 mol), bromocyclopropane (6.05 g,0.05 mol), cesium carbonate (16.29 g,0.05 mol), palladium acetate (0.29 g,1.3 mmol), 2- (di-tert-butylphosphine) -3, 6-dimethoxy-2 '-4' -6 '-tri-1-propyl-1, 1' -biphenyl (1.94 g,4 mmol) are added into 1, 4-dioxane (200 ml), the temperature is controlled to 75-80 ℃, after the reaction is detected, the reaction solution is filtered while hot through diatomite, the filtrate is cooled to room temperature, purified water (1500 ml) is added for extraction, methyl tert-butyl ether (500 ml multiplied by 3) is added, the organic phases are combined, saturated brine (500 ml multiplied by 2) is washed, and the organic phases are concentrated to dryness, thus obtaining the target compound I, the yield is 87.3%, and the purity is 98.88%.
Example 30
Under the protection of argon, compound I-3 (19.34 g,0.05 mol), bromocyclopropane (9.68 g,0.08 mol), cesium carbonate (32.58 g,0.1 mol), palladium acetate (1.12 g,5 mmol), 2- (di-tert-butylphosphine) -3, 6-dimethoxy-2 '-4' -6 '-tri-1-propyl-1, 1' -biphenyl (5.82 g,12 mmol) are added into dimethyl sulfoxide (200 ml), the temperature is controlled between 110 and 115 ℃ for reaction, after the reaction is detected, the reaction solution is filtered while the reaction solution is hot and is filled with diatomite, the filtrate is cooled to room temperature, added into purified water (1500 ml), methyl tertiary butyl ether (500 ml multiplied by 3) is extracted, an organic phase is combined, saturated saline (500 ml multiplied by 2) is washed, and the organic phase is concentrated to dryness under reduced pressure, thus obtaining the target compound I, the yield is 86.2%, and the purity is 98.45%.

Claims (10)

1. A method for preparing lenvatinib, which is characterized by comprising the following steps:
step 1: adding compound SM-1, compound SM-2 and alkali A into reaction solvent A at room temperature, and controlling temperature T A After the reaction is finished, preparing an intermediate compound I-1 through post-treatment;
step 2: adding compound I-1 and organolithium into tetrahydrofuran, and controlling temperature T B After stirring evenly, adding compound SM-3, continuing to control temperature T B After stirring evenly, adding catalyst and continuing controlling temperature T B After the reaction is finished, preparing an intermediate compound I-2 through post-treatment;
step 3: adding the compound I-2 into trifluoroacetic acid, and controlling the temperature T C After the reaction is finished, the reaction solution is decompressed and concentrated to remove most of the solvent, then the reaction solution is neutralized to pH value of more than 7 by saturated sodium bicarbonate, the organic solvent is extracted, the organic phase is combined, the organic phase is washed by saturated saline, and the organic phase is decompressed and concentrated to dryness to obtain an intermediate compound I-3;
step 4: under the protection of inert gas, adding the compound I-3, bromocyclopropane, alkali D, catalyst and ligand into the reaction solvent D, and controlling the temperature T D After the reaction is finished, preparing the compound I through post-treatment;
the reaction route is as follows:
2. the method according to claim 1, wherein the base A in step 1 is one selected from potassium hydroxide, N-diisopropylethylamine, triethylamine, N-methylmorpholine, potassium carbonate, potassium tert-butoxide, and sodium methoxide.
3. A process for producing according to claim 1,the method is characterized in that the reaction solvent A in the step 1 is one of N, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide, acetonitrile or N-methylpyrrolidone; temperature control T in step 1 A 60-100 ℃.
4. The preparation method according to claim 1, wherein the molar ratio of the compound SM-1 to the compound SM-2 to the base a in step 1 is 1:1.1 to 1.6:2.5 to 5.0.
5. The method according to claim 1, wherein the organolithium in step 2 is selected from one of n-butyllithium, sec-butyllithium and phenyllithium.
6. The method according to claim 1, wherein the catalyst in step 2 is one selected from the group consisting of cuprous bromide, cuprous chloride and cupric bromide.
7. The preparation method according to claim 1, wherein the molar ratio of the compound I-1 to the compound SM-3, the organolithium and the catalyst in the step 2 is 1:1.3 to 2.0:1.0 to 1.4:0.8 to 1.3.
8. The preparation method according to claim 1, wherein the mass-to-volume ratio of the compound I-2 to trifluoroacetic acid in the step 3 is 1: 6-12 g/ml; reaction temperature T in step 3 C 50-69 ℃.
9. The method according to claim 1, wherein the catalyst in step 4 is selected from one or a combination of palladium acetate and palladium chloride; the ligand in the step 4 is 2- (di-tert-butylphosphine) -3, 6-dimethoxy-2 '-4' -6 '-tri-1-propyl-1, 1' -biphenyl.
10. The process according to claim 1, wherein the step 4 comprises reacting I-3 with bromocyclopropane, a base D,The feeding mole ratio of the catalyst to the ligand is 1:1.05 to 1.5:1.0 to 1.8:0.03 to 0.08:0.1 to 0.2; the reaction solvent D in the step 4 is one or a combination of dimethyl sulfoxide, 1, 4-dioxane and water; the reaction temperature T D Is 80-110 ℃.
CN202310825186.3A 2023-07-06 2023-07-06 Preparation method of lenvatinib Pending CN117343007A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202310825186.3A CN117343007A (en) 2023-07-06 2023-07-06 Preparation method of lenvatinib

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202310825186.3A CN117343007A (en) 2023-07-06 2023-07-06 Preparation method of lenvatinib

Publications (1)

Publication Number Publication Date
CN117343007A true CN117343007A (en) 2024-01-05

Family

ID=89358232

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202310825186.3A Pending CN117343007A (en) 2023-07-06 2023-07-06 Preparation method of lenvatinib

Country Status (1)

Country Link
CN (1) CN117343007A (en)

Similar Documents

Publication Publication Date Title
CN110204487B (en) Synthesis method of quinoline derivative
JP7368636B2 (en) Method for synthesizing roxadustat and its intermediates and intermediates thereof
CN111704573B (en) Preparation method of rabeprazole chloride and intermediate thereof
CN111057070A (en) Synthesis method of baroxavir key intermediate
CN110483549B (en) Preparation method of nitroimidazole pyran antituberculosis drug
CN108997214A (en) It is happy to cut down for Buddhist nun's intermediate and its preparation and the happy preparation cut down for Buddhist nun
CN102659494A (en) Method for asymmetric synthesis of 3,3-disubstituted-2-oxindole compound
CN107602570B (en) Method for synthesizing nitrogen-containing multi-membered heterocyclic compound
CN107118215B (en) A kind of preparation method for treating breast cancer medicines Rui Boxini intermediate
CN117343007A (en) Preparation method of lenvatinib
CN114671867B (en) Preparation method of tocartinib intermediate 7-hydroxy- [1,2,4] triazolo [1,5-a ] pyridine
CN111349045A (en) Synthetic method of lenvatinib and novel intermediate
CN111704558B (en) Method for preparing phenyl-2- (2' -cyanophenyl) acetylene compounds by palladium catalysis
CN109134351B (en) Synthesis method of S-3- (4-aminophenyl) piperidine
CN116239531A (en) Preparation method of lenvatinib
CN109748809B (en) Method for synthesizing 2-substituted amino-1, 4-naphthoquinone derivative
CN108503600B (en) Polysubstituted quinoxaline derivative and preparation method thereof
CN117624044A (en) Preparation method of lenvatinib
CN106349182B (en) The preparation method of bis- substitutions of 4,5--thiazolamine compound
CN110423224B (en) Synthesis method of 2-aminopyrimidine type antiplatelet compound
CN116283761B (en) 3-Alkenyl ketone substituted quinoline-2-ketone and green synthesis method thereof
CN112457243B (en) Synthesis method of 7-bromo-5-methoxyquinoline
CN115477635A (en) Preparation method of rasemiptan
CN111718301B (en) Synthetic method of quinazolinone derivative
CN112457245B (en) Synthesis method of 7- (trifluoromethyl) isoquinoline-5-amine

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination